Vaccine development is an empirical process, governed by response rates, efficacy studies, side effects and the duration of protection; data gleaned experimentally from large, longitudinal clinical studies. This program develops novel high-resolution molecular metrics that define the mechanisms that mediate long-term protective memory B cell responses after norovirus (NoV) vaccination. Using human vaccine samples, we will: i) characterize broadly protective antibody responses using in vitro and in vivo (mice) models, ii) measure the magnitude of the short and long-term neutralizing antibody response, iii) map key epitopes linked with long- term protective immunity, and iv) deconstruct the B cell memory response associated with homotypic and heterotypic protective immunity after vaccination. As rapidly evolving viruses complicate vaccine development, our technologies and approaches will have wide applicability for global health. NoV are the major cause of acute non-bacterial, epidemic gastroenteritis and cause millions of infections that result in ~200,000 deaths/year, globally. To prevent future NoV outbreaks, we will identify molecular markers for long-term protective immunity after vaccination. Our studies will identify key NoV neutralizing epitopes which mediate type specific and broadly cross reactive short and long-term protective immunity and memory B cell responses following human vaccination and 3) inform second generation NoV vaccine design. The platform technologies developed here are readily portable to other systems. Important outcomes include the identification of key epitopes associated with cross neutralizing, long-term protective immunity across GI and across GII strains, the identification of key barriers to vaccine performance in humans, and the emergence of novel solutions to ameliorate these barriers to effective human NoV vaccine design.